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Dual Inhibition

Hypercholesterolaemia is a condition where the levels of cholesterol in the blood are too high. Elevated levels of one cholesterol in particular, low-density lipoprotein cholesterol (sometimes referred to as ‘bad cholesterol), can cause problems by building up in the inner walls of the arteries that feed the heart and brain. Together with other substances it can form a plaque, a thick, hard deposit that can clog those arteries and lead to heart diseases and stroke. ‘Dual inhibition’ describes a type of drug therapy that uses both statins and Ezetimibe to lower cholesterol. Together, these drugs seem to be more effective at helping people reduce cholesterol than just one drug alone.

What is cholesterol?

Cholesterol is a waxy, fat-like substance that is naturally found in the walls of the body’s cells. The level of cholesterol in the body is determined by two things: the amount of cholesterol that we absorb in our intestines, and the amount that we produce in our liver. Having some cholesterol in the body is normal and healthy – we need it to produce certain hormones, vitamin D, and bile acids that help to digest fat. But if we have too much cholesterol, it can build up in arteries and lead to coronary heart disease and many other serious conditions. There are two major types of cholesterol found in the blood: low-density lipoprotein (LDL) cholesterol, sometimes referred to as ‘bad’ cholesterol, and high-density lipoprotein (HDL) cholesterol, or ‘good’ cholesterol.

Low density lipoprotein (LDL) cholesterol is called ‘bad’ because it is a major contributor to the development of atherosclerosis – the sticky plaques that can form inside blood vessels and contribute to problems like stroke.

High density lipoprotein (HDL) is ‘good’ because it helps remove cholesterol from these developing plaques, taking it back to the liver to be excreted from the body in bile. Levels of HDL in the body can be raised by things like exercise, and lowered by smoking.

What is a ‘normal’ cholesterol level? There is no simple answer to this question – we still don’t know exactly how much of each type of cholesterol is ‘good’ for us. The National Heart Foundation and The Cardiac Society of Australia and New Zealand give the following target levels:

Total cholesterol < 4.0 mmol/L

LDL-cholesterol < 2.5 mmol/L

HDL-cholesterol > 1.0 mmol/L

These numbers indicate a level to aim for in patients with other risk factors for coronary heart disease, such as a family history of the disease, or diabetes mellitus. In people with no other risk factors, safe levels may be slightly higher. In general, though, it is healthier to have low levels of LDL-cholesterol and high levels of HDL-cholesterol.

What is dual inhibition?

Dual inhibition refers to a type treatment that lowers LDL cholesterol by two different methods at once. A patient on dual inhibition therapy will be taking two drugs: one called a statin and another called ezetimibe.How does dual inhibition work?
The first drug, the statin, reduces the amount of LDL-cholesterol that we make in the liver, and also increases the amount of cholesterol that the liver ‘clears out’ of the blood as it passes through. The second drug, ezetimibe, acts by reducing the amount of cholesterol absorbed from the intestines. This means that less cholesterol is taken in to the body, and so less can make its way into the bloodstream. With both of these drugs working together, there is less cholesterol being taken in to the body, less cholesterol being made in the liver, and more cholesterol being ‘filtered’ out of the blood. Overall, blood levels of LDL-cholesterol are lowered.Why use it?
Dual inhibition therapy may be useful when one drug alone is not effective in lowering LDL-cholesterol. For example, most of the effect of a statin occurs at the recommended starting dose; doubling the dose after that will only produce an additional benefit of 6%. Ezetimibe has a different sort of action to a statin, so adding the two together can have a more beneficial effect on cholesterol levels than simply increasing the dose of the statin.How effective is dual inhibition?
Several studies have recently been conducted to look at the effectiveness of dual therapy at lowering LDL-C levels, such as the Ezetimibe Add-on to Statin for Effectiveness (EASE) trial. These trials have consistently shown that the combination of a statin and ezetimibe is more effective at lowering cholesterol than a statin alone – in one trial, reductions of up to 61% were seen in levels of LDL-cholesterol. Dual therapy was also very effective at helping patients reach their target blood lipid levels. New findings have also shown that dual inhibition therapy can benefit patients with diabetes mellitus, metabolic syndrome, or metabolic lipid abnormality. For example, nearly 93% of diabetic patients receiving ezetimibe together with a statin reached their LDL-C goals.Is dual inhibition safe?
Ezetimibe is a generally safe drug and is well tolerated by most people. It may produce some mild side effects, including headache and diarrhoea. It rarely interacts with other drugs to cause adverse reactions. Statins have a few important side effects. Common problems include headache, nausea and vomiting, constipation, diarrhoea, or rash. A more serious but rare side effect is called rhabdomyolysis, where breakdown of muscle cells occurs, resulting in muscle pain and weakness. Another important side effect which may be caused by both ezetimibe and statins is changes in liver function. This means that dual inhibition therapy may not be safe to use in people who have a liver problem such as liver failure or cirrhosis. Dual inhibition therapy, where ezetimibe is combined with a statin, has been demonstrated in a number of trials to be well tolerated. Side effects are minimal, almost similar to those of statin treatment alone.For more information about Dual inhibition talk to your doctor.

Reduction in Cardiovascular Risk – Lower is better through dual inhibition. Highlights from the 2004 European Society of Cardiology Congress and the 2004 European Association for the Study of Diabetes Annual Meeting; 2004 Aug 28-Sep 9; Munich, Germany.